tbuckley/cabot-search huggingface dataset:
Abstract LB066: Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A
Authors: Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li
Journal: Cancer Research (2023)

Abstract Hypoxia-inducible factor 1 alpha (HIF1A) activation drives cellular adaption to low oxygen stress in malignant and non-malignant cells. HIF1A transcriptionally regulates many genes in key processes like angiogenesis and metastasis, facilitating the cell’s survival. Interestingly, HIF1A is able to carry out its regulatory functions by forming protein-protein interactions with its co-transcription factors. Since low oxygen conditions are frequently present in cancerous cells, we predict that these co-transcription factors could serve as new cancer therapeutic targets. Our recent work has thus focused on identifying motifs in HIF1A ChIP-Seq sequences and discovering novel HIF1A co-transcription factors. In this study, we leveraged cutting-edge deep learning methods, including a hybrid convolutional neural network (CNN) and recurrent neural network (RNN) based motif-discovery model, and discovered several novel motifs. We also look to predict potential therapeutic drugs against the identified co-transcription factors using a machine-learning drug discovery model that evaluates therapies based on their half-maximal inhibitory concentration (IC50). We have so far found several small molecules that could adequately modulate the activity of the identified co-transcription factors. Our results could lead to new therapeutic approaches against HIF1A-dependent cancers such as colon, breast, gastric, lung, brain, and prostate. Citation Format: Yuxiang Zhang, Saidi Wang, Haiyan Hu, Xiaoman Li. Machine learning algorithm for drug discovery targeting new co-transcription factors of HIF1A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB066.
Abstract LB210: RenNano® mice: A heavy-chain-only antibody platform for the generation of nanobody therapeutics
Authors: Yiqing Hu, Qi Zhang, Lijun Zhang, Yabo Zhang, Huizhen Zhao, Jiawei Yao, Liu Yang, Baihong Liu, Shensen Wang, Zhengfang Su, Li Hui, Qingcong Lin, Qiangqiang Ma, Yuelei Shen
Journal: Cancer Research (2023)

Abstract Monoclonal antibodies have been used to successfully treat various diseases, including tumors, autoimmune diseases, and infectious diseases. Traditional antibodies are comprised of a tetramer of two heavy chains and two light chains, totaling 150 kDa in molecular weight. However, the large size of antibodies can limit the therapeutic application; in particular, the penetration of tumors and the blood brain barrier (BBB) is not always feasible. In contrast to traditional antibodies, heavy-chain-only antibodies (HCAbs) are significantly smaller (~75 kDa), as they contain only two heavy chains. Since the heavy chain variable domain of HCAbs (i.e., VHH or single domain antibody, sdAb, or nanobody) is solely responsible for antigen recognition, nanobodies can function independently as a therapeutic molecule, which may be advantageous for penetrating tumors or the BBB. Previously, we generated a fully human antibody mouse platform, RenMabTM, in which the murine heavy chain and kappa light chain variable domains were replaced by the full human heavy chain and kappa light chain V(D)J loci in situ. Here, we have further modified the RenMabTM model to generate a fully human heavy-chain-only antibody mouse model, termed RenNano®. The modified heavy chain constant regions of RenNano® mice allow them to spontaneously produce HCAbs. Flow cytometry and biolayer interferometry confirmed that RenNano®-derived HCAbs can bind antigens without light chains. Despite this reliance on the heavy chain only variable regions for antigen specificity, RenNano® mice can generate antigen-specific antibodies with high affinity (10−8 -10−9 KD) upon immunization with various antigens. In addition, many RenNano®-derived HCAbs exhibited a longer CDR3 length, which could promote the recognition of difficult-to-reach epitopes. Furthermore, RenNano®-derived HCAbs have favorable diversity, and excellent developability properties such as a higher degree of hydrophilicity. Anti-4-1BB HCAbs can also activate 4-1BB-NF-κB signaling in a dose-dependent manner, as demonstrated in reporter assays. In summary, the full human heavy-chain-only antibody mice, RenNano®, can produce human HCAb with high affinity and good efficacy. Thus, RenNano® is a powerful platform to discover HCAb/nanobodies for various therapeutic applications. Citation Format: Yiqing Hu, Qi Zhang, Lijun Zhang, Yabo Zhang, Huizhen Zhao, Jiawei Yao, Liu Yang, Baihong Liu, Shensen Wang, Zhengfang Su, Li Hui, Qingcong Lin, Qiangqiang Ma, Yuelei Shen. RenNano® mice: A heavy-chain-only antibody platform for the generation of nanobody therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB210.
Abstract LB069: Predictive modeling of drug sensitivity based on the genetic dependency
Authors: Bicna Song, Lumen Chao, Xiaolong Cheng, Yuan Gao, Ruocheng Shan, Wei Li
Journal: Cancer Research (2023)

Abstract Functional genetic screens have been frequently used to repurpose existing drugs or to identify new drug targets. However, the associations between hits on screens and candidate drugs have been unclear, and a manual approach to directly infer drug candidates from “druggable” candidates suffers from its laborious, ad hoc investigation and low accuracy. Here, we describe a systematic approach to explore the associations between genetic dependencies and drug sensitivity of cancer cell lines and to identify potential drug repositioning opportunities. We first developed drug sensitivity predictive models trained on genome-wide CRISPR-Cas9 knockout viability profiles and large-scale drug response screens of 4,518 drugs from DepMap. We obtained the highest predictive power from the decision-tree-based models and observed previously reported associations between gene perturbation and drug response. For example, cancer cells that are more sensitive to TP53 or MDM2 perturbation were more sensitive to MDM inhibitors, and EGFR or ERBB2 dependency strongly predicted the sensitivity of cells to EGFR inhibitors. Interestingly, for 3,260 drugs with known targets, only 1.5% of these genes were selected as top features to predict drug sensitivity, indicating that genes that are not the direct targets of drugs should be considered. In addition, we applied our models to the CRISPR-Cas9 knockout screens that target 1,805 “druggable” genes and predicted the sensitivity of cancer cells to known and novel drugs. Furthermore, we were able to validate the candidate drugs using cell viability assays. Finally, a multi-class classification deep learning model, based on the TorchDrug framework, reaches higher recall values than a decision-tree-based method but with much lower precision values. Our study provided the first systematic evaluation between large-scale gene dependency and drug responses. The machine learning predictive model provides an in-silico approach to perform drug screens from functional genetic screens. Citation Format: Bicna Song, Lumen Chao, Xiaolong Cheng, Yuan Gao, Ruocheng Shan, Wei Li. Predictive modeling of drug sensitivity based on the genetic dependency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB069.
Abstract LB013: Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival
Authors: Praveen Agrawal
Journal: Cancer Research (2023)

Abstract Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma survival, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that alpha-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding alpha-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon alpha–2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that alpha-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors. Citation Format: Praveen Agrawal. Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB013.
Abstract LB059: DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer
Authors: Maria Zhivagui, Areebah Hoda, Noelia Valenzuela, Yi-yu Yeh, Jason Dai, Yudou He, Shuvro P. Nandi, Burcak Otlu, Bennett Van Houten, Ludmil Alexandrov
Journal: Cancer Research (2023)

Abstract Ultraviolet A (UVA) rays are long wavelengths that can penetrate the deeper layer of the skin and are responsible for the immediate tanning effect. A multitude of natural and artificial sources of UV exposure exist, including UV-emitting lamps that are commonly used in dentistry, cosmetics, and medical laboratories. Recently, several reports suggested that long-term use of UV-nail polish dryers, used for curating nail polish formulas, known as gel, may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation released by UV-nail polish dryers on mammalian cells. Here, we address the continuous exposure of clients and employees to UVA light by employing both murine and human primary cell models for irradiation, in an acute and chronic manner, using a UV-dryer machine. We, then, subject the cells to DNA sequencing either by bulk whole-genome sequencing after clonal expansion or by single-molecule duplex sequencing without clonal expansion. Our findings show that UVA-exposed samples manifest an increase of C:G&amp;gt;A:T transversions compared to control cells. The patterns of mutations found in these cells can be recapitulated by mutational signatures previously attributed to reactive oxygen species (ROS), namely COSMIC signatures SBS18/36. These results are further corroborated by the presence of high levels of ROS in irradiated samples, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Importantly, we show that in contrast to UVB exposure, UVA does not induce an increase of C:G&amp;gt;T:A transitions, indicating that different types of ultraviolet light radiation affect DNA through distinctive molecular mechanisms. Finally, re-examination of somatic mutations from skin cancers reported by the International Cancer Genome Consortium (ICGC) reveals that SBS18/36 are ubiquitously present in melanoma and account for 12% of the previously annotated driver mutations. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells. Citation Format: Maria Zhivagui, Areebah Hoda, Noelia Valenzuela, Yi-yu Yeh, Jason Dai, Yudou He, Shuvro P. Nandi, Burcak Otlu, Bennett Van Houten, Ludmil Alexandrov. DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB059.
Abstract LB037: Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene
Authors: Jilong Chen, Yun Ma
Journal: Cancer Research (2023)

Abstract Chronic myeloid leukemia (CML) is a hematological malignancy mainly caused by the Bcr-Abl oncogene that results from the reciprocal translocation between human chromosome 9 and 22, and occurs in more than 90% of CML cases. Bcr-Abl oncogene is also involved in tumorigenesis of other leukemia such as acute lymphoid leukemia (ALL). Although progress has been made in the understanding of signal transduction in Abl-mediated transformation, the molecular mechanisms underlying Abl-induced tumorigenesis are still not fully understood. It is well known that imatinib treatment can greatly suppress Bcr-Abl-mediated development of leukemia, but intracellular molecules induced by imatinib and their roles in the tumorigenesis remain largely to be determined. On the other hand, the majority of human transcripts lack protein-coding capacity, which are defined as noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) play important roles in various vital biological processes. Notably, increasing number of lncRNAs have been linked to human diseases, including cancers. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Here, we identified several imatinib-induced lncRNAs as critical regulator of Bcr-Abl-induced tumorigenesis. Most of these lncRNAs expressed in a very low levels in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, they could be significantly induced in Abl-positive leukemic cells treated by imatinib. Silencing these lncRNAs promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of particular lncRNAs sensitized the cells to apoptosis and suppressed tumor growth. In concert, knockout of some murine lncRNAs in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, some lncRNA deficient mice were generated, and we observed that knockout of particular murine lncRNAs facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA deficiency promoted Abl-transformed cell survival and development of leukemia in mice. In summary, these findings unveil an inhibitory role of several critical lncRNAs in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis. Citation Format: Jilong Chen, Yun Ma. Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB037.
Abstract LB172: Improved T-cell and B-cell receptor repertoire profiling and immunophenotyping for biomarker discovery
Authors: Alex Chenchik, Mikhail Makhanov, Tianbing Liu, Dongfang Hu, Paul Diehl, Lester Kobzik
Journal: Cancer Research (2023)

Abstract T-cell receptor (TCR) and B-cell receptor (BCR) repertoire profiling, also referred to as adaptive immune receptor repertoire (AIRR) profiling, holds great potential for the understanding of disease mechanisms and for the development of new treatments in infectious disease, autoimmunity, and immuno-oncology. This potential could be greatly improved by combining information about receptor clonotypes with immunophenotypes of T- and B- cells. A new technology we developed that combines profiling of all human TCR and BCR variable regions with phenotypic characterization of immune cells using the same workflow could be particularly useful. The TCR and BCR immunophenotyping method proposed involves RT-PCR amplification and sequencing of the CDR3 regions of the TCR and BCR genes, and subsequently determining the expression levels of the most informative T- and B-cell phenotyping genes. Preliminary results show that this method allows for comprehensive profiling of all seven TCR and BCR chains from a single sample, in a highly reproducible manner, directly from micro-samples including cancer tissue, whole blood, sorted cells and more. Bioinformatic analysis of the next-generation sequencing (NGS) data from the TCR and BCR clonotypes profile combined with RNA expression profiling of the same samples results in a richer data set that includes the identification of major immune cell subtypes and their activation status. Data from human cancer tissue and whole blood samples will be presented. Citation Format: Alex Chenchik, Mikhail Makhanov, Tianbing Liu, Dongfang Hu, Paul Diehl, Lester Kobzik. Improved T-cell and B-cell receptor repertoire profiling and immunophenotyping for biomarker discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB172.
Britain's first minister of public health
Authors: J. Powles, N. Day, K. McPherson, M. McKee, T. McMichael, I. Chalmers, G. D. Smith, J. Gabbay, D. Marks, I. Sharp, R. Wilkinson, M. Marmot, J. Crown, M. Clarke, S. Griffiths
Journal: BMJ (1997)
The Tattletape Tale
Authors: Ralph S. Crawshaw
Journal: JAMA (1978)

PHYSICIANS treat cynicism in medicine much as they do the weather, with much talk and little action. Yet, unlike the weather, cynicism can become a predictable, constructive force, especially when used to focus moral light on an existing evil. In fact, physicians could go so far as to teach medical students positive cynicism, the examination of human values, the sharing of the self-evident truth that no thinking physician successfully completes his daily rounds without some touch of that special cast of mind, and the sharp vision of things as they are, which a cynic uses to clarify and purify social values. <h3>A Shrine to Disbelief</h3> An example of constructive cynicism in the service of higher professional standards occurred when a shrine to disbelief in positive human values was erected on our local health-science campus. It is an archway under which all students and faculty must pass, genuflecting in token of
Near-Death Experiences
Authors: Ian Stevenson
Journal: JAMA (1979)

DURING the last two decades, articles and books about death and dying have proliferated, but, with rare exceptions, their authors ignore completely the question of whether man survives after death. One of us (I.S.) recently has reviewed the evidence that suggests man's survival after death.<sup>1</sup>The evidence available is far from necessitating a conclusion in favor of such survival, but it is also far from deserving the neglect it has received from most scientists. One type of research that may contribute to this evidence is the investigation of neardeath experiences—reports of persons who come close to death but escape. Such experiences include those of persons who are seriously injured or ill and are expected to die or are thought to be dead, but who unexpectedly recover. Also relevant are the experiences of persons who anticipate death during a potentially fatal situation, such as a fall from a great height,
Laparoscopic common bile duct exploration through the cystic duct using flexible cholangioscopy combined with cholecystectomy for managing cholecysto-choledocholithiasis
Authors: Wengang Zhang, Hui Ding, Zhenjuan Li, Enqiang Linghu
Journal: Endoscopy (2023)

Common bile duct (CBD) stones are present in approximately 3 % to 16 % patients with symptomatic gallstones [1] [2] [3]. Laparoscopic common bile duct exploration (LCBDE) and laparoscopic cholecystectomy (LC) could treat cholecysto-choledocholithiasis in one session. However, some drawbacks including the unsatisfactory controllability of the surgical choledochoscope, postoperative bile leak, and the use of the T-tube have hindered the further development of LCBDE + LC. To solve these problems, we introduced LCBDE through the cystic duct using a more flexible cholangioscope combined with cholecystectomy for cholecysto-choledocholithiasis.
Cleft palate: a rare complication following esophageal stent implantation
Authors: Wei Liu, Ou Chen, Lifan Zhang, Bing Hu
Journal: Endoscopy (2023)

A 50-year-old woman was referred to our hospital because of increasing dysphagia. She had been diagnosed with systemic lupus erythematosus 2 years previously and started on treatment with tacrolimus and corticosteroids. Multiple diverticula of the esophagus were confirmed and the largest diverticulum was located next to the cardia. Esophagogram showed delayed passage of contrast into the stomach, and gastroscopy revealed a dilated esophagus with retained liquid and increased resistance at the cardia ([Fig. 1 a–c]). The patient refused to undergo endoscopic or surgical myotomy as she was concerned about the treatment risks. Therefore, esophageal stent implantation was believed to be an option for this case.
Sixty seconds on . . . pandemic preprints
Authors: Gareth Iacobucci
Journal: BMJ (2023)

There were a lot of themAt one stage during the pandemic it felt like covid-19 preprint papers outnumbered even batches of homemade banana bread.But a research letter 1 published in JAMA has reported that 1 in 5 preprint abstracts from random controlled trials posted to medRxiv during the pandemic were unpublished for at least 12 months after posting. What happened? Lost down the back of the sofa?The authors reported that those preprints that didn't see the light of the day were "less complete and more highly spun than preprints that progressed to publication." Spin doctors?We're not talking Alastair Campbell or Dominic Cummings here.But in research terms, the study team observed examples where the preliminary results that were emphasised may not have been backed up by the data. Spinning tops?Quite the opposite.The authors noted that in some instances, covid-19 treatment protocols were adopted based on "erroneous preprints."